Sulfonamide matrix metalloproteinase inhibitors

ABSTRACT

Matrix metalloproteinase inhibitors are tricyclic substituted cyclic sulfonamides of the formula  
                 
 
     or a pharmaceutically acceptable salt thereof wherein R 1  and R 2  include hydrogen, alkyl, and substituted alkyl; R 3  and R 4  include hydrogen, halo, and alkyl; X is OH or NHOH, V is O, S, SO 2 , NR 5 , or CH 2 , R 5  is a hydrogen or alkyl, and Z is (CH 2 ) n , wherein n is an integer from 0 to 2.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of priority from U.S. provisionalapplication No. 60/268,737, filed Feb. 14, 2001.

FIELD OF THE INVENTION

[0002] This invention relates to a group of cyclic sulfonamide compoundsand derivatives that inhibit matrix metalloproteinase enzymes and thusare useful for treating diseases resulting from tissue breakdown, suchas heart disease, multiple sclerosis, arthritis, atherosclerosis, andosteoporosis.

BACKGROUND OF THE INVENTION

[0003] Matrix metalloproteinases (sometimes referred to as MMPs) arenaturally occurring enzymes found in most mammals. Over-expression andactivation of MMPs or an imbalance between MMPs and inhibitors of MMPshave been suggested as factors in the pathogenesis of diseasescharacterized by the breakdown of extracellular matrix or connectivetissues.

[0004] Stromelysin-1 and gel atinase A are members of the MMP family.Other members include fibroblast collagenase (MMP-1), neutrophilcollagenase (MMP-8), gelatinase B (92 kDa gelatinase) (MMP-9),stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), matrilysin (MMP-7),collagenase 3 (MMP-13), TNF-alpha converting enzyme (TACE), and othernewly discovered membrane-associated matrix metalloproteinases (Sato H.,Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., Seiki M.,Nature, 1994;370:61-65). These enzymes have been implicated in a numberof diseases which result from breakdown of connective tissue; includingsuch diseases as rheumatoid arthritis, osteoarthritis, osteoporosis,periodontitis, multiple sclerosis, gingivitis, corneal epidermal andgastric ulceration, atherosclerosis, neointimal proliferation whichleads to restenosis and ischemic heart failure, and tumor metastasis. Amethod for preventing and treating these and other diseases is nowrecognized to be by inhibiting metalloproteinase enzymes, therebycurtailing and/or eliminating the breakdown of connective tissues thatresults in the disease states.

[0005] The catalytic zinc in matrix metalloproteinases is typically thefocal point for inhibitor design. The modification of substrates byintroducing zinc chelating groups has generated potent inhibitors suchas peptide hydroxamates and thiol-containing peptides. Peptidehydroxamates and the natural endogenous inhibitors of MMPs (TIMPs) havebeen used successfully to treat animal models of cancer andinflammation. MMP inhibitors have also been used to prevent and treatcongestive heart failure and other cardiovascular diseases. For example,see U.S. Pat. No. 5,948,780.

[0006] The need to find new low-molecular weight compounds that arepotent MMP inhibitors, and that have an acceptable therapeutic index oftoxicity/potency to make them amenable for clinical use in theprevention and treatment of the associated disease states, continues. Anobject of this invention is to provide a group of MMP inhibitorscharacterized as being sulfonamides bearing a tricyclic aromatic orheteroaromatic substituent.

SUMMARY OF THE INVENTION

[0007] This invention provides a group of tricyclic substitutedsulfonamide compounds that are inhibitors of matrix metalloproteinaseenzymes. The invention is more particularly directed to compoundsdefined by Formula I

[0008] or the pharmaceutically acceptable salts thereof wherein:

[0009] R¹ and R² independently are hydrogen or C₁-C₆ alkyl;

[0010] R³ and R⁴ independently are hydrogen, halo, nitro, NR⁵R⁶, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl; (CH₂)_(m) OH, (CH₂)_(m) OR⁵,(CH₂)_(m) cycloalkyl, (CH₂)_(m) aryl, (CH₂)_(m) substituted aryl,(CH₂)_(m) heteroaryl, (CH₂)_(m) substituted heteroaryl, (CH₂)_(m)carbocycle, (CH₂)_(m) heterocycle; (CH₂)_(m) NR⁵R⁶, (CH₂)_(m) COR⁵,(CH₂)_(m) CONR⁵R⁶, or (CH₂)_(m) CO₂R⁵;

[0011] m is an integer from 0 to 6;

[0012] R⁵ and R⁶ independently are hydrogen or C₁-C₆ alkyl, or takentogether with the nitrogen to which they are attached complete a 3- to7-membered ring;

[0013] Z is (CH₂)_(n);

[0014] n is 0, 1, or 2;

[0015] Y is S, SO, or SO₂;

[0016] X is OH or NHOH;

[0017] V is O, S, SO₂, NH, NR⁵, or CH₂.

[0018] Another invention embodiment is a compound of Formula II

[0019] or a pharmaceutically acceptable salt thereof, wherein R¹, R²,R³, V, and X are as defined above.

[0020] Another invention embodiment is a compound of Formula II, or apharmaceutically acceptable salt thereof, wherein R³ is halo.

[0021] Another invention embodiment is a compound of Formulas I or II,or a pharmaceutically acceptable salt thereof, wherein X is OH.

[0022] Another invention embodiment is a compound of Formulas I or II,or a pharmaceutically acceptable salt thereof, wherein X is NHOH.

[0023] Another invention embodiment is a compound of Formula III

[0024] or a pharmaceutically acceptable salt thereof, wherein R¹, R²,R³, and X are as defined above.

[0025] Another invention embodiment is a compound of Formula IV

[0026] or a pharmaceutically acceptable salt thereof, wherein R¹, R²,R³, and X have the above defined meanings.

[0027] Another invention embodiment is a compound of Formula V

[0028] or a pharmaceutically acceptable salt thereof, wherein R¹, R²,R³, and X are as defined above.

[0029] Another invention embodiment is a compound of Formula VI

[0030] or a pharmaceutically acceptable salt thereof, wherein R¹, R²,R³, and X are as defined above.

[0031] Another invention embodiment is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein Y is SO₂.

[0032] Another invention embodiment is a compound of Formula VII

[0033] or a pharmaceutically acceptable salt thereof, wherein V, Z, X,R¹, and R² are as defined above for Formula I.

[0034] A further embodiment of this invention is a pharmaceuticalcomposition, comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, admixed with a pharmaceutically acceptablecarrier, excipient, or diluent.

[0035] Another invention embodiment is a pharmaceutical composition,comprising a compound of any one of Formulas II through VII, or apharmaceutically acceptable salt thereof, admixed with apharmaceutically acceptable carrier, excipient, or diluent.

[0036] Another invention embodiment is a pharmaceutical composition,comprising a compound selected from:

[0037](S)-4-(Dibenzofuran-3-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid;

[0038](S)-4-(Dibenzofuran-3-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0039]R-3-(Dibenzofuran-3-sulfonyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid;

[0040]R-3-(Dibenzofuran-3-sulfonyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid hydroxyamide;

[0041](S)-4-(9H-Fluorene-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid;

[0042](S)-4-(9H-Fluorene-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0043](S)-4-(Dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid;

[0044](S)-4-(Dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0045](S)-4-(7-Bromo-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid;

[0046](S)-4-(7-Bromo-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0047](S)-4-(7-Methoxycarbonyl-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid;

[0048](S)-4-(7-Methoxycarbonyl-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0049](S)-2,2-Dimethyl-4-(7-nitro-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid;

[0050](S)-2,2-Dimethyl-4-(7-nitro-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;

[0051](S)-4-(Dibenzofuran-2-sulfonyl)-2,2-dimethyl-1,1-dioxo-thiomorpholine-3-carboxylicacid hydroxyamide;

[0052](S)-4-(7-Isobutyrylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid;

[0053](S)-2,2-Dimethyl-4-[7-(3-phenyl-propionylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid;

[0054](S)-2,2-Dimethyl-4-[7-(4-methyl-pentanoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid;

[0055](S)-4-(7-Benzoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid;

[0056](S)-2,2-Dimethyl-4-(7-propionylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid;

[0057](S)-4-[7-(3-Ethyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid;

[0058](S)-4-[7-(3-Isopropyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid;

[0059](S)-2,2-Dimethyl-4-[7-(3-phenyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid;

[0060](S)-4-[7-(3,3-Diethyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid;

[0061](S)-4-[7-(2,4-Dichloro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carbxoylicacid hydroxyamide;

[0062](S)-4-[7-(3,4-Dimethoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0063](S)-4-[7-(2,5-Dimethoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0064](S)-2,2-Dimethyl-4-(7-phenylacetylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;

[0065](S)-2,2-Dimethyl-4-{7-[(thiophene-2-carbonyl)-amino]-dibenzofuran-2-sulfonyl}-thiomorpholine-3-carboxylicacid hydroxyamide;

[0066](S)-4-[7-(3-Ethyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0067](S)-4-[7-(3-Isopropyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0068](S)-2,2-Dimethyl-4-[7-(3-phenyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0069](S)-4-[7-(3,3-Diethyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0070]2,2-Dimethyl-4-[7-(3-nitro-benzoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0071]4-(7-Dodecanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0072]N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-oxalamicacid ethyl ester;

[0073]4-[7-(Cyclohexanecarbonyl-amino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0074]4-[7-(2-Fluoro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0075]4-(7-Acetylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0076] Acetic acid2-[8-(3-hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-ylcarbamoyl]-phenylester;

[0077]4-(7-Benzoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0078]4-(7-Butyrylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0079]4-(7-Decanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0080]4-(7-Decanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0081]4-(7-Diphenylacetylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0082]4-{7-[2-(4-Chloro-phenoxy)-acetylamino]-dibenzofuran-2-sulfonyl}-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0083]N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-succinamicacid methyl ester;

[0084]4-[7-(3,4-Dimethoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0085]4-[7-(2-Methoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0086]4-[7-(2,2-Dimethyl-pentanoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0087]4-[7-(2,4-Dichloro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0088]4-[7-(2,5-Dimethoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0089]2,2-Dimethyl-4-[7-(4-methyl-pentanoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0090]4-[7-(Cyclopropanecarbonyl-amino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0091] Acetic acid[8-(3-hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-ylcarbamoyl]-phenyl-methylester;

[0092]2,2-Dimethyl-4-{7-[(tricyclo[3.3.1]decanane-1-carbonyl)-amino]-dibenzofuran-2-sulfonyl}-thiomorpholine-3-carboxylicacid hydroxyamide;

[0093]2,2-Dimethyl-4-(7-pentanoylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;

[0094]4-[7-(2,2-Dimethyl-propionylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0095]2,2-Dimethyl-4-[7-((Z)-octadec-9-enoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0096]N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-succinamicacid ethyl ester;

[0097]4-(7-Isobutyrylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0098]4-(7-Isobutyrylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0099]4-[7-(3-Chloro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0100]2,2-Dimethyl-4-(7-nonanoylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;

[0101]2,2-Dimethyl-4-[7-(2-trifluoromethyl-benzoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0102]2,2-Dimethyl-4-[7-(2-trifluoromethyl-benzoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0103]2,2-Dimethyl-4-(7-octanoylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;

[0104]4-(7-Hexadecanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0105]4-(7-Hexadecanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0106]2,2-Dimethyl-4-[7-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-octanoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0107]2,2-Dimethyl-4-[7-(2-phenoxy-acetylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0108]2,2-Dimethyl-4-[7-(2-phenoxy-acetylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0109]2,2-Dimethyl-4-(7-phenylacetylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;

[0110]2,2-Dimethyl-4-(7-propionylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;

[0111]2,2-Dimethyl-4-(7-tridecanoylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;

[0112]4-[7-(3,5-Dinitro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0113]N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-malonamicacid ethyl ester;

[0114]N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-malonamicacid ethyl ester;

[0115]2,2-Dimethyl-4-[7-(2,2,2-trichloro-acetylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0116]2,2-Dimethyl-4-{7-[(thiophene-2-carbonyl)-amino]-dibenzofuran-2-sulfonyl}-thiomorpholine-3-carboxylicacid hydroxyamide;

[0117]2,2-Dimethyl-4-[7-(3-phenyl-propionylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide; and

[0118]4-[7-(2-Bromo-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide, or a pharmaceutically acceptable salt thereof,admixed with a pharmaceutically acceptable carrier, diluent, orexcipient.

[0119] Another embodiment of this invention is a method for inhibitingMMP enzymes in an animal, comprising administering to the animal an MMPinhibiting amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof.

[0120] A further embodiment is a method for treating a disease mediatedby an MMP enzyme, comprising administering to a patient suffering fromsuch disease an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

[0121] Another invention embodiment is a method for treating a cancer,comprising administering to a patient suffering from such a disease ananticancer effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

[0122] Another invention embodiment is a method for treating breastcarcinoma, comprising administering to a patient suffering from such adisease an anticancer effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

[0123] Another invention embodiment is a method for treating arheumatoid arthritis, comprising administering to a patient sufferingfrom such a disease an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

[0124] Another invention embodiment is a method for treating aosteoarthritis, comprising administering to a patient suffering fromsuch a disease an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

[0125] Another invention embodiment is a method for treating a heartfailure, comprising administering to a patient suffering from such adisease an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

[0126] Another invention embodiment is a method for treating ainflammation, comprising administering to a patient suffering from sucha disease an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

[0127] Another embodiment of this invention is use of a compound ofclaim 1, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of a disease mediated byan MMP enzyme.

[0128] Another invention embodiment is use of a compound of claim 1, ora pharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of cancer.

[0129] Another invention embodiment is use of a compound of claim 1, ora pharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of arthritis.

[0130] Another invention embodiment is use of a compound of claim 1, ora pharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of rheumatoid arthritis.

[0131] Another invention embodiment is use of a compound of claim 1, ora pharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of osteoarthritis.

[0132] Another invention embodiment is use of a compound of claim 1, ora pharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of congestive heart failure.

DETAILED DESCRIPTION OF THE INVENTION

[0133] The compounds provided by this invention are those defined byFormula I. In Formula I, R¹-R⁴ include “C₁-C₆ alkyl” groups. These arestraight and branched carbon chains having from 1 to 6 carbon atoms.Examples of such alkyl groups include methyl, ethyl, isopropyl,tert.-butyl, neopentyl, and n-hexyl. The alkyl groups can be substitutedif desired, for instance with groups such as hydroxy, amino, alkyl, anddialkylamino, halo, trifluoromethyl, carboxy, nitro, and cyano.

[0134] “Halo” includes fluoro, chloro, bromo, and iodo.

[0135] “Alkenyl” means straight and branched hydrocarbon radicals havingfrom 2 to 6 carbon atoms and one double bond and includes ethenyl,3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl, and the like.

[0136] “Alkynyl” means straight and branched hydrocarbon radicals havingfrom 2 to 6 carbon atoms and 1 triple bond and includes ethynyl,3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like.

[0137] “Cycloalkyl” means a monocyclic or polycyclic hydrocarbyl groupsuch as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl,adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, andcyclopentyl. Such groups can be substituted with groups such as hydroxy,keto, and the like. Also included are rings in which 1 to 3 heteroatomsreplace carbons. Such groups are termed “heterocyclyl”, which means acycloalkyl group also bearing at least one heteroatom selected from O,S, or NR², examples being oxiranyl, pyrrolidinyl, piperidyl,tetrahydropyran, and morpholine.

[0138] “Alkoxy” refers to the alkyl groups mentioned above bound throughoxygen, examples of which include methoxy, ethoxy, isopropoxy,tert-butoxy, and the like. In addition, alkoxy refers to polyethers suchas —O—(CH₂)₂—O—OH₃, and the like.

[0139] “Alkanoyl” groups are alkyl linked through a carbonyl, i.e.,C₁-C₅—C(O)—. Such groups include formyl, acetyl, propionyl, butyryl, andisobutyryl.

[0140] “Acyl” means an alkyl or aryl (Ar) group bonded through acarbonyl group, i.e., R—C(O)—, where R is alkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, all optionally substituted. For example,acyl includes a C₁-C₆ alkanoyl, including substituted alkanoyl, whereinthe alkyl portion can be substituted by NR⁵R⁶ or a carboxylic orheterocyclic group. Typical acyl groups include acetyl, benzoyl, and thelike.

[0141] The alkyl, alkenyl, alkoxy, and alkynyl groups described aboveare optionally substituted, preferably by 1 to 3 groups selected fromNR⁵R⁶, phenyl, substituted phenyl, thio C₁-C₆ alkyl, C₁-C₆ alkoxy,hydroxy, carboxy, C₁-C₆ alkoxycarbonyl, halo, nitrile, cycloalkyl, and a5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2heteroatoms selected from nitrogen, substituted nitrogen, oxygen, andsulfur. “Substituted nitrogen” means nitrogen bearing C₁-C₆ alkyl or(CH₂)_(n)Ph where n is 1, 2, or 3. Perhalo and polyhalo substitution isalso embraced.

[0142] Examples of substituted alkyl groups include 2-aminoethyl,pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl,2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl,methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl,4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl,3-morpholinopropyl, piperazinylmethyl, and 2-(4-methylpiperazinyl)ethyl.

[0143] Examples of substituted alkynyl groups include 2-methoxyethynyl,2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl),3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl,4-cyclobutyl-4-hexenyl, and the like.

[0144] Typical substituted alkoxy groups include aminomethoxy,trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy,3-hydroxypropoxy, 6-carboxhexyloxy, and the like.

[0145] Further, examples of substituted alkyl, alkenyl, and alkynylgroups include dimethylaminomethyl, carboxymethyl,4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl,4-morpholinobutyl, 4-tetrahydropyrinidylbutyl,3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl,3-chlorophenylmethyl, and the like.

[0146] As noted above, R⁴ and R⁵ include hydrogen, alkyl, and aryl.Examples of NR⁴R⁵ groups include amino, methylamino, di-isopropylamino,acetyl amino, propionyl amino, 3-aminopropyl amino, 3-ethylaminobutylamino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl amino, and3-carboxypropionyl amino. R⁴ and R⁵ can be taken together with thenitrogen to which they are attached to form a ring having 3 to 7 carbonatoms and 1, 2, or 3 heteroatoms selected from the group consisting ofnitrogen, substituted nitrogen, oxygen, and sulfur. Examples of suchcyclic NR⁴R⁵ groups include pyrrolidinyl, piperazinyl,4-methylpiperazinyl, 4-benzylpiperazinyl, pyridinyl, piperidinyl,pyrazinyl, morpholinyl, and the like.

[0147] The terms “Ar” and “aryl” refer to unsubstituted and substitutedaromatic groups. Heteroaryl groups have from 4 to 9 ring atoms, from 1to 4 of which are independently selected from the group consisting of O,S, and N. Preferred heteroaryl groups have 1 or 2 heteroatoms in a 5- or6-membered aromatic ring. Mono- and bicyclic aromatic ring systems areincluded in the definition of aryl and heteroaryl. Typical aryl andheteroaryl groups include phenyl, 3-chlorophenyl, 2,6-dibromophenyl,pyridyl, 3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl,4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl,4,7-dichloronaphthyl, morpholinyl, indolyl, benzotriazolyl, indazolyl,pyrrole, pyrazole, imidazole, thiazole, and the like.

[0148] Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or3 groups independently selected from the group consisting of alkyl,alkoxy, thio, thioalkyl, halo, hydroxy, —COOR⁷, trifluoromethyl, nitro,amino of the formula —NR⁵R⁶, and T(CH₂)_(m)QR⁵ or T(CH₂)_(m)CO₂R⁵wherein m is 1 to 6, T is O, S, NR⁵, N(O)R⁵, NR⁵R⁶Z, or CR⁵R⁶, Q is O,S, NR⁵, N(O)R⁵, or NR⁴R⁵R⁶Y wherein R⁴, R⁵, and R⁶ are as describedabove, R⁷ is alkyl or substituted alkyl, for example, methyl,trichloroethyl, diphenylmethyl, and the like, and Z is a counter ionsuch as chloride or bromide. The alkyl and alkoxy groups can besubstituted as defined above. For example, typical groups arecarboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, andalkoxyalkyl.

[0149] The term “patient” means a mammal. Preferred patients includehumans, cats, dogs, cows, horses, pigs, and sheep.

[0150] The term “animal” means a mammal. Preferred animals includehumans, rats, mice, guinea pigs, rabbits, monkeys, cats, dogs, cows,horses, pigs, and sheep.

[0151] The phrases “therapeutically effective amount” and “effectiveamount” are synonymous unless otherwise indicated, and mean an amount ofa compound of the present invention that is sufficient to improve thecondition, disease, or disorder being treated. Determination of atherapeutically effective amount, as well as other factors related toeffective administration of a compound of the present invention to apatient in need of treatment, including dosage forms, routes ofadministration, and frequency of dosing, may depend upon the particularsof the condition that is encountered, including the patient andcondition being treated, the severity of the condition in a particularpatient, the particular compound being employed, the particular route ofadministration being employed, the frequency of dosing, and theparticular formulation being employed. Determination of atherapeutically effective treatment regimen for a patient is within thelevel of ordinary skill in the medical or veterinarian arts. In clinicaluse, an effective amount may be the amount that is recommended by theUnited States Food and Drug Administration, or an equivalent foreignagency.

[0152] The phrase “admixed” or “in admixture” means the ingredients somixed comprise either a heterogeneous or homogeneous mixture. Preferredis a homogeneous mixture.

[0153] The phrases “pharmaceutical preparation” and “preparation” aresynonymous unless otherwise indicated, and include the formulation ofthe active compound with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers,is surrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Pharmaceuticalpreparations are fully described below.

[0154] The phrase “anticancer effective amount” means an amount ofinvention compound, or a pharmaceutically acceptable salt thereof,sufficient to inhibit, halt, or cause regression of the cancer beingtreated in a particular patient or patient population. For example inhumans or other mammals, an anticancer effective amount can bedetermined experimentally in a laboratory or clinical setting, or may bethe amount required by the guidelines of the United States Food and DrugAdministration, or equivalent foreign agency, for the particular cancerand patient being treated.

[0155] The phrase “MMP-13 inhibiting amount” means an amount ofinvention compound, or a pharmaceutically acceptable salt thereof,sufficient to inhibit an enzyme matrix metalloproteinase-13, including atruncated form thereof, including a catalytic domain thereof, in aparticular animal or animal population. For example in a human or othermammal, an MMP-13 inhibiting amount can be determined experimentally ina laboratory or clinical setting, or may be the amount required by theguidelines of the United States Food and Drug Administration, orequivalent foreign agency, for the particular MMP-13 enzyme and patientbeing treated.

[0156] It should be appreciated that the matrix metalloproteinasesinclude the following enzymes:

[0157] MMP-1, also known as interstitial collagenase, collagenase-1, orfibroblast-type collagenase;

[0158] MMP-2, also known as gelatinase A or 72 kDa Type IV collagenase;

[0159] MMP-3, also known as stromelysin or stromelysin-1;

[0160] MMP-7, also known as matrilysin or PUMP-1;

[0161] MMP-8, also known as collagenase-2, neutrophil collagenase, orpolymorphonuclear-type (“PMN-type”) collagenase;

[0162] MMP-9, also known as gelatinase B or 92 kDa Type IV collagenase;

[0163] MMP-10, also known as stromelysin-2;

[0164] MMP-11, also known as stromelysin-3;

[0165] MMP-12, also known as metalloelastase;

[0166] MMP-13, also known as collagenase-3;

[0167] MMP-14, also known as membrane-type (“MT”) 1-MMP or MT1-MMP;

[0168] MMP-15, also known as MT2-MMP;

[0169] MMP-16, also known as MT3-MMP;

[0170] MMP-17, also known as MT4-MMP;

[0171] MMP-18; and

[0172] MMP-19.

[0173] Other MMPs are known, including MMP-26, which is also known asmatrilysin-2.

[0174] The term “IC₅₀” means the concentration of test compound requiredto inhibit activity of a biological target, such as a receptor orenzyme, by 50%.

[0175] The phrase “a method for inhibiting MMP enzymes” includes methodsof inhibiting full-length MMP enzymes, truncated forms thereof thatretain catalytic activity, including forms that contain the catalyticdomains of the MMP enzymes, as well as the catalytic domains of the MMPenzymes alone, and truncated forms of the catalytic domains that retainat least some catalytic activity.

[0176] It should be appreciated that it has been shown previously (YeQi-Zhuang, et al., supra, 1996) that inhibitor activity against acatalytic domain of an MMP is predictive of the inhibitor activityagainst the respective full-length enzyme.

[0177] The compounds to be used in the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention. Several of the compounds have one or more chiralcenters, and as such can exist as racemates and pure enantiomers. Alloptical isomers and positional isomers are included in the scope of thisinvention.

[0178] The compounds of Formulas I through VII are capable of furtherforming both pharmaceutically acceptable salts, including but notlimited to acid addition and/or base salts, solvents and N-oxides of acompound of Formulas I through VII. This invention also providespharmaceutical formulations comprising a compound of Formulas I throughVII together with a pharmaceutically acceptable carrier, diluent, orexcipient therefor. All of these forms can be used in the method of thepresent invention.

[0179] Pharmaceutically acceptable acid addition salts of the compoundsof Formulas I through VII include salts derived form inorganic acidssuch as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic,hydroiodic, phosphorus, and the like, as well as the salts derived fromorganic acids, such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Suchsalts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,propionate, caprylate, isobutyrate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Also contemplated arethe salts of amino acids such as arginate, gluconate, galacturonate, andthe like; see, for example, Berge et al., “Pharmaceutical Salts,” J. ofPharmaceutical Science, 1977;66:1-19.

[0180] The acid addition salts of the basic compounds are prepared bycontacting the free-base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free-base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free-base forms differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but otherwise the salts areequivalent to their respective free base for purposes of the presentinvention.

[0181] Pharmaceutically acceptable base addition salts are formed withmetals or amines, such as alkali and alkaline earth metal hydroxides, orof organic amines. Examples of metals used as cations are sodium,potassium, magnesium, calcium, and the like. Examples of suitable aminesare N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methylglucamine, and procaine. Forexample, see Berge et al., supra, 1977.

[0182] The base addition salts of acidic compounds are prepared bycontacting the free-acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner. The free-acid formmay be regenerated by contacting the salt form with an acid andisolating the free acid in a conventional manner. The free-acid formsdiffer from their respective salt forms somewhat in certain physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid for purposes of the presentinvention.

[0183] The compounds of the present invention can be formulated andadministered in a wide variety of oral and parenteral dosage forms,including transdermal and rectal administration. All that is required isthat an MMP inhibitor be administered to a mammal suffering from adisease in an effective amount, which is that amount required to causean improvement in the disease and/or the symptoms associated with suchdisease. It will be recognized by those skilled in the art that thefollowing dosage forms may comprise as the active component, either acompound of Formulas I through VII, or a corresponding pharmaceuticallyacceptable salt or solvate of a compound of Formulas I through VII.

[0184] A compound of Formula I, or a pharmaceutically acceptable saltthereof, may be prepared by one of ordinary skill in the art of organicchemistry by procedures found in the chemical literature such as, forexample, Reagents for Organic Synthesis by Fieser and Fieser, New York:2000, John Wiley & Sons, Inc.; Comprehensive Organic Transformations, byRichard C. Larock, VCH Publishers, Inc., New York, 1989; the seriesCompendium of Organic Synthetic Methods by Wiley-Interscience, 1989; thetext Advanced Organic Chemistry, 5^(th) edition, by Jerry March, NewYork: 2001, Wiley-Interscience; or the Handbook of HeterocyclicChemistry, by Alan R. Katritzky, London: Pergamon Press Ltd, 1985, toname a few. Alternatively, a skilled artisan may find methods useful forpreparing the invention compounds in the chemical literature bysearching widely available databases such as, for example, thoseavailable from the Chemical Abstracts Service, Columbus, Ohio, or MDLInformation Systems GmbH (formerly Beilstein Information Systems GmbH),Frankfurt, Germany.

[0185] Preparations of the compounds of the present invention may usestarting materials, reagents, solvents, and catalysts that may bepurchased from commercial sources or they may be readily prepared byadapting procedures in the references or resources cited above.Commercial sources of starting materials, reagents, solvents, andcatalysts useful in preparing invention compounds include, for example,The Aldrich Chemical Company, and other subsidiaries of Sigma-AldrichCorporation, St. Louis, Mo., BACHEM, BACHEM A.G., Switzerland, orLancaster Synthesis Ltd, United Kingdom.

[0186]Reagents for Organic Synthesis, by Fieser and Fieser, New York,John Wiley & Sons, Inc., 2000; Comprehensive Organic Transformations, byRichard C. Larock, VCH Publishers, Inc., New York, 1989; the seriesCompendium of Organic Synthetic Methods by Wiley-Interscience, 1989; thetext Advanced Organic Chemistry, 5^(th) edition, by Jerry March,Wiley-Interscience, New York 2001; and the Handbook of HeterocyclicChemistry, by Alan R. Katritzky, Pergamon Press Ltd., London, 1985 arehereby incorporated by reference.

[0187] The compounds of the invention are prepared by methods well knownto those skilled in the art of organic chemistry. The compounds ofFormula I are prepared utilizing commercially available startingmaterials, or reactants that are readily prepared by standard organicsynthetic techniques. A typical synthesis of the invention compounds ofFormula I is shown in Scheme 1 below. The first step in Scheme 1comprises reacting a tricyclic aromatic or heteroaromatic sulfonylchloride (1) with a substituted thiomorpholine carboxylic acid ester(2). These reactants are generally combined in approximately equimolarquantities in a mutual organic solvent such as dichloromethane, and inthe presence of an acid scavenger such as triethylamine. Generally, thereaction is substantially complete within about 2 to 8 hours whencarried out at a temperature of about 20° C. to 60° C. The product, asulfonamide ester of Formula I (3), can be isolated if desired byremoving the reaction solvent by evaporation; and can be purified ifdesired by recrystallization from solvents such as ethyl acetate andhexane. The sulfonamide ester (3) is next hydrolyzed by reaction with astrong acid such as trifluoroacetic acid, generally in the presence of afree radical scavenger. such as anisole. The sulfonamide acid (4) isgenerally isolated by simply removing the reaction solvent, and it canbe crystallized or chromatographed if desired. The sulfonamidecarboxylic (4, where X is OH) acid can be converted to the hydroxamicacid (5, where X is NHOH) by reaction with oxalyl chloride to form thecorresponding acid chloride in situ, and then reaction with excesshydroxylamine in the presence of a base such as sodium bicarbonate.

[0188] The thiomorpholines of Formula I wherein Y is S are readilyconverted to the corresponding sulfoxides and sulfones (where Y is SOand SO2) by oxidation with a peracid such as peracetic acetic acid ormetachloroperbenzoic acid. This is shown in Scheme 1 (5 to 5).

[0189] The invention compounds of Formula I are ideally suited tosynthesis by general combinatorial methodologies. Schemes 2 and 3illustrate the use of resin supports to facilitate the rapid synthesisof invention compounds. As shown in Scheme 2, a tricyclic-thiomorpholinecarboxylic acid (4) is reacted with an acylating agent such as a benzoylhalide to form a mixed anhydride, which is then reacted in situ with asolid resin (e.g., a polystyrene resin “PS” such as a commerciallyavailable Wang resin) through the oxygen atom to provide atricyclic-thiomorpholine carboxylic acid bound to a resin support(compound 8 in Scheme 2). Functional groups at other sites in themolecule (e.g., R³ and R⁴) can be modified by standard methods toprovide invention compounds. For example, when R³ of Formula I compoundsis a nitro group, it is readily reduced by reaction with a standardreducing agent such as tin chloride to provide the corresponding aminoanalog (8). The amino group can be acylated by reaction with a commonacylating agent such as an acid chloride to give an N-aryl analog ofFormula I (a). Alternatively, the amino group can be reacted with anisocyanate RNCO to give ureas of Formula I (10). Thetricyclic-thiomorpholine carboxylic acid is readily liberated from theWang resin by reaction with a strong acid such as trifluoroacetic acid(to give 9 or 10).

[0190] Scheme 3 illustrates the use of a hydroxylamine resin to preparehydroxamic acids of Formula I (X=NHOH). A tricyclic-thiomorpholinecarboxylic acid (4 where X=OH) is first activated at the carboxy groupby reaction with a peptide coupling reagent such asdicyclohexylcarbodiimide (DCC) or 1,3-diisopropylcarbodiimide. Theactivated tricyclic-thiomorpholine carboxylic acid is then reacted witha hydroxylamine resin, generally in the presence of a base such as4-dimethylaminopyridine (DMAP), to form the resin-bound hydroxamic acidanalog (11). Modifications at other sites in the molecule can be carriedout as described above in Scheme 2 (nitro groups reduced to aminogroups, amino groups alkylated or acylated, etc). Following suchmodifications, the tricyclic-thiomorpholine hydroxamic acid is readilyliberated from the resin by simple acid hydrolysis, for example byreaction with trifluoroacetic acid or the like.

[0191] Scheme 4 illustrates the further modification of ringsubstituents or the tricyclic portion of the compounds of Formula I. Thescheme starts with a halo (Br) substituted tricyclic analog that iscarbomylated by reaction with carbon monoxide in the presence of asuitable catalyst to produce an alkoxycarbonyl substituted analog. Thealkoxycarbonyl group is reduced to a hydroxymethyl group by reactionwith a reducing agent such as sodium borohydride. The hydroxymethylgroup is converted to a mesyloxymethyl group by reaction withmethanesulfonyl chloride (MSCl). The mesyloxy group is readily displacedby reaction with a nucleophile such as an amine (HNR⁵R⁶) to affordvarious invention compounds of Formula I. As described above, thethiomorpholine carboxylic acids (X=OH) are readily converted tohydroxamic acids (X=NHOH) by reaction with hydroxylamine, or the entireforegoing sequence can be carried out on a hydroxylamine resin asdescribed in Scheme 3.

[0192] During the synthesis of some of the invention compounds, it maybe desirable to protect reactive functional groups such as hydroxy,amino, and carboxylic groups, so as to avoid unwanted side reactions.The use of protecting groups in synthetic organic chemistry iswell-established and is fully described by Greene and Wuts in“Protecting Groups in Organic Synthesis” (John Wiley & Son Press, 3^(rd)ed). Examples of common amino protecting groups include acyl groups suchas formyl and acetyl, and arylalkyl groups such as benzyl. Typicalhydroxy protecting groups include ether forming groups such as methyland ethyl, and acyl groups such as acetyl and tert-butoxycarbonyl(tBOC). Carboxylic acids generally are protected as esters, for example2,2,2-trichloroethyl and benzyl. These protecting groups are readilycleaved by standard methods when desired.

[0193] Sulfoxides and sulfones of Formula 1, wherein n is 1 or 2, areprepared by oxidation of the corresponding sulfides with one or twoequivalents of an oxidizing agent such as peracetic acid ormeta-chloroperbenzoic acid.

[0194] The following detailed examples further illustrate the synthesisof typical invention compounds of Formula I. The examples arerepresentative only and are not to be construed as limiting theinvention in any respect. All references cited herein are incorporatedby reference.

EXAMPLE 1

[0195](S)-4-(Dibenzofuran-3-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid

[0196] (a) To a solution of 3-dibenzofuransulfonyl chloride (1 g, 3.75mmol) and 3(S)-2,2-dimethyl-3-thiomorpholine carboxylic acid,1,1-dimethylether ester hydrochloride (1 g, 3.75 mmol) in 40 mL ofdichloromethane was added triethylamine (1 mL). The solution was stirredat room temperature overnight, then added to 50 mL of water. The organiclayer was separated, washed with brine, dried (MgSO4), filtered, and thesolvent was removed by evaporation under reduced pressure. The crudeproduct was recrystallized from hexane/ethyl acetate to give 0.68 g of(S)-4-(dibenzofuran-3-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid tert-butyl ester. ¹HNMR (DMSO-d₆) δ8.4 (d, 1H), 8.3 (d, 1H), 8.0(s, 1H), 7.8 (m, 2H), 7.6 (t, 1H), 4.3 (s, 1H), 4.1 (dd, 1H), 3.7 (tt,1H), 2.9 (tt, 1H), 2.6 (dd, 1H), 1.5 (s, 3H), 1.3 (s, 3H), 1.1 (s, 9H)ppm.

[0197] (b) The ester obtained in (a) (0.5 g, 1.08 mmol) was dissolved indichloromethane (5 mL) to which was added one equivalent of anisole (0.1mL, 1.08 mmol) and trifluoroacetic acid (5 mL). The solution was stirredat room temperature overnight and concentrated in vacuo. The crudeproduct was recrystallized from hexane/ethyl acetate to give 0.42 g ofthe title compound. ¹HNMR (DMSO-d₆) δ8.4 (d, 1H), 8.3 (d, 1H), 8.0 (s,1H), 7.8 (m, 1H), 7.6 (t, 1H), 7.5 (t, 1H), 4.3 (s, 1H), 4.1 (d, 1H),3.7 (tt, 1H), 3.0 (tt, 1H), 2.5 (d, 1H), 1.5 (s, 3H), 1.3 (s, 3H) ppm.

EXAMPLE 2

[0198](S)-4-(Dibenzofuran-3-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide

[0199] A dichloromethane solution of the acid synthesized in Example 1(0.26 g, 0.64 mmol/10 mL CH2Cl2) was reacted with oxalyl chloride (0.1mL, 0.77 mmol) and a catalytic amount of N,N-dimethylformamide under anatmosphere of nitrogen. After stirring at room temperature for 30minutes, the solution was concentrated in vacuo. The crude acid chloridewas dissolved in tetrahydrofuran and added to a tetrahydrofuran (60mL)/water (20 mL) solution containing hydroxylamine hydrochloride (0.44g, 6.4 mmol) and sodium bicarbonate (0.81 g, 9.6 mmol). The reactionmixture was stirred at room temperature overnight, then concentrated invacuo. The crude product was diluted with ethyl acetate and washed withwater, brine, dried (MgSO₄), and concentrated. The resulting residue wasrecrystallized from hexane/ethyl acetate to give 0.14 g of the titlecompound.

EXAMPLES 3-4

[0200] Replacement of 3(S)-2,2-dimethyl-3-thiomorpholine carboxylicacid, 1,1-dimethylethyl ester hydrochloride withR-5,5-dimethyl-thiazolidine-4-carboxylic acid tert-butyl ester andfollowing the experimental conditions described for Examples 1 and 2yield the following compounds:

EXAMPLE 3

[0201]R-3-(Dibenzofuran-3-sulfonyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid.

[0202]¹HNMR (DMSO-d₆) δ8.4 (d, 1H), 8.3 (d, 1H), 8.2 (s, 1H), 7.9 (d,1H), 7.8 (d, 1H), 7.7 (t, 1H), 7.5 (t, 1H), 4.7 (dd, 2H), 4.1 (s, 1H),1.3 (s, 3H), 1.2 (s, 3H) ppm.

EXAMPLE 4

[0203]R-3-(Dibenzofuran-3-sulfonyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid hydroxyamide.

[0204]¹HNMR (DMSO-d₆) δ10.8 (s, 1H), 9.1 (s, 1H), 8.4 (d, 1H), 8.3 (d,1H), 8.1 (s, 1H), 7.9 (d, 1H), 7.8 (d, 1H), 7.6 (t, 1H), 7.5 (t, 1H),4.7 (s, 2H), 3.8 (s, 1H), 1.3 (s, 3H), 1.0 (s, 3H) ppm.

EXAMPLES 5-6

[0205] Replacement of 3-dibenzofuransulfonyl chloride with2-fluorenesulfonyl chloride and utilizing the experimental conditionsdescribed in Example 1 and Example 2 gave the following compounds:

EXAMPLE 5

[0206](S)-4-(9H-Fluorene-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid.

[0207]¹HNMR (DMSO-d₆) δ12.8 (bs, 1H), 8.1 (d, 1H), 8.0 (d, 1H), 7.9 (s,1H), 7.7 (d, 1H), 7.6 (d, 1H), 7.4 (m, 2H), 4.3 (s, 1H), 4.0 (d, 1H),3.7 (tt, 1H), 2.9 (tt, 1H), 2.5 (d, 1H), 1.5 (s, 3H), 1.3 (s, 3H) ppm.

EXAMPLE 6

[0208](S)-4-(9H-Fluorene-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide.

EXAMPLES 7-8

[0209] Replacement of 3-dibenzofuransulfonyl chloride with2-dibenzofuransulfonyl chloride and utilizing the experimentalconditions described in Examples 1 and 2 gave the following compounds:

EXAMPLE 7

[0210](S)-4-(Dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid.

[0211]¹HNMR (DMSO-d₆) δ8.6 (s, 1H), 8.3 (d, 1H), 7.8 (m, 2H), 7.7 (d,1H), 7.6 (t, 1H), 7.5 (t, 1H), 4.3 (s, iH), 4.1 (d, 1H), 3.7 (t, 1H),2.9 (t, 1H), 2.5 (d, 1H), 1.5 (s, 3H), 1.3 (s, 3H) ppm.

EXAMPLE 8

[0212](S)-4-(Dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide.

[0213]¹HNMR (DMSO-d₆) δ10.7 (s, 1H), 8.8 (s, 1H), 8.6 (s, 1H), 8.3 (d,1H), 7.9 (m, 2H), 7.8 (d, 1H), 7.6 (t, 1H), 7.5 (t, 1H), 4.1 (s, IH),4.0-3.9 (m, 2H), 2.9 (tt, 1H), 2.5 (d, 1H), 1.4 (s, 3H), 1.1 (s, 3H)ppm.

EXAMPLES 9-14

[0214] Replacement of 2-dibenzofuransulfonyl chloride in Example 7 withappropriately substituted dibenzofuran derivatives yield the followinganalogs:

EXAMPLE 9

[0215]9.(S)-4-(7-Bromo-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid.

[0216]¹HNMR (DMSO d₆) δ12.7 (s, 1H), 8.7 (s, 1H), 8.3 (d, 1H), 8.1 (s,1H), 7.9 (m, 2H), 7.7 (d, 1H), 4.3 (s, 1H), 4.0 (d, 1H), 2.9 (t, 1H),2.5 (d, 1H), 1.4 (s, 3H), 1.2 (s, 3H) ppm.

EXAMPLE 10

[0217](S)-4-(7-Bromo-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide.

[0218]¹HNMR (DMSO-d₆) δ10.7 (s, 1H), 8.9 (s, 1H), 8.6 (s, 1H), 8.2 (d,1H), 8.1 (s, iH), 7.9 (m, 2H), 7.7 (d, 1H), 4.1 (s, 1H), 4.0-3.8 (m,2H), 2.9 (t, iH), 2.6 (d, 1H), 1.4 (s, 3H), 1.1 (s, 3H) ppm.

EXAMPLE 11

[0219](S)-4-(7-Methoxycarbonyl-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid.

[0220]¹HNMR (DMSO-d₆) δ12.7 (s, 1H), 8.7 (s, 1H), 8.5 (d, 1H), 8.3 (s,1H), 8.1 (d, 1H), 7.9 (m, 2H), 4.3 (s, 1H), 4.1 (d, 1H), 3.9 (s, 3H),3.7 (t, 1H), 2.9 (t, 1H), 2.6 (d, 1H), 1.4 (s, 3H), 1.2 (s, 3H) ppm.

EXAMPLE 12

[0221](S)-4-(7-Methoxycarbonyl-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide.

[0222]¹HNMR (DMSO-d₆) δ10.7 (s, 1H), 8.8 (s, 1H), 8.7 (s, 1H), 8.4 (d,1H), 8.3 (s, 1H), 8.1 (d, 1H), 7.9 (m, 2H), 4.1 (s, 1H), 4.0 (m, 2H),3.9 (s, 3H), 2.9 (t, 1H), 2.6 (d, 1H), 1.4 (s, 3H), 1.2 (s, 3H) ppm.

EXAMPLE 13

[0223](S)-2,2-Dimethyl-4-(7-nitro-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid.

[0224]¹HNMR (DMSO-d₆) δ8.4 (d, 2H), 8.3 (d, 1H), 8.1 (d, 1H), 7.9 (d,1H), 7.7 (d, 1H), 4.4 (s, 1H), 4.0 (d, 1H), 3.8 (t, 1H), 3.1 (t, 1H),2.4 (d, 1H), 1.6 (s, 3H), 1.3 (s, 3H) ppm.

EXAMPLE 14

[0225](S)-2,2-Dimethyl-4-(7-nitro-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide.

[0226]¹HNMR (DMSO-d₆) δ10.7 (s, 1H), 8.8 (s, 1H), 8.7 (s, 1H), 8.5 (d,1H), 8.4 (d, 1H), 7.9 (m, 2H), 4.1 (s. 1H), 4.0 (m, 2H), 2.9 (t, 1H),2.5 (d, 1H), 1.4 (s, 3H), 1.2 (s, 3H) ppm.

EXAMPLE 15

[0227](S)-4-(Dibenzofuran-2-sulfonyl)-2,2-dimethyl-1,1-dioxo-thiomorpholine-3-carboxylicacid hydroxyamide

[0228] To a chloroform solution of the compound prepared in Example 8(0.052 g, 0.124 mmol/5 mL CHCl₃) stirred at room temperature undernitrogen was added dropwise peracetic acid. Dissolution occurredfollowed by precipitation. The reaction mixture was stirred at roomtemperature overnight, then concentrated in vacuo. The resulting residuewas recrystallized from hexane/ethyl acetate to give 0.32 g of thetitled sulfone. ¹H R (DMSO-d₆) δ10.6 (s, 1H), 9.0 (bs, 1H), 8.6 (s, 1H),8.3 (d, 1H), 8.9-8.7 (m, 3H), 7.6 (t, 1H), 7.5 (t, 1H), 4.7 (t, 1H), 5.5(s, 1H), 3.5-3.2 (m, 2H), 1.4 (s, 3H), 1.3 (s, 3H) ppm.

EXAMPLES 16-24

[0229] General Procedure Utilizing Solid Phase Synthesis to ObtainCarboxylic Acid Derivatives (Scheme 2)

[0230] (a) To a suspension of Wang resin (2 g, 2.8 mmol) in 20 mL ofdimethylformamide was added the acid 4 (2.2 g, 5.6 mmol) dissolved in 5mL of dimethylformamide followed by the addition of pyridine (560 μL,8.4 mmol) and 2,6-dichlorobenzoyl chloride (650 μL, 5.6 mmol). After themixture was shaken for 22 hours at room temperature, the modified resinwas filtered, washed 4×20 mL with dimethylformamide and 4×20 mL withdichloromethane, and dried under vacuum overnight to give resin 7.

[0231] (b) To 100 mg of modified resin 7 (0.93 mmol) was added 2 mL of 1M tin (II) chloride dihydrate in dimethylformamide. After the reactionmixture was shaken for 16 hours at 50° C., the resin was filtered,washed 4×2 mL with dimethylformamide and 4×2 mL with dichloromethane,and dried under vacuum overnight to give resin 8.

[0232] (c) To the resin 8 was added 2 mL of 0.2 M acid chloride indichloromethane and 0.5 mL of 0.4 M triethylamine in dichloromethane.After shaking for 16 hours at room temperature, the resin mixture wasfiltered, washed 3×2 nL with dichloromethane, 3×2 mL with methanol, 3×2mL with dimethylformamide, 3×2 mL with dichloromethane, and dried undervacuum overnight. The final product 9 was obtained by the addition of 2mL of 50% trifluoroacetic acid in dichloromethane. After 1 hour ofshaking, the filtrate was collected and the solvent was removed undervacuum to give crude 9. The products are purified using silica gelchromatography and characterized by LC-MS.

EXAMPLE 16

[0233](S)-4-(7-Isobutyrylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid

EXAMPLE 17

[0234](S)-2,2-Dimethyl-4-[7-(3-phenyl-propionylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid

EXAMPLE 18

[0235](S)-2,2-Dimethyl-4-[7-(4-methyl-pentanoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid

EXAMPLE 19

[0236](S)-4-(7-Benzoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid

EXAMPLE 20

[0237](S)-2,2-Dimethyl-4-(7-propionylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid

[0238] General Procedure for Urea Formation (Scheme 2).

[0239] To the resin 8 was added 2 mL of 0.2 M isocyanate in dioxane.After shaking for 16 hours at 80° C., the resin mixture was filtered,washed 4×2 mL with dimethylformamide and 4×2 mL with dichloromethane,and dried under vacuum overnight. A solution of CH₂Cl₂/TFA (50%) wasthen added to the dried resin. The mixture was stirred for 3 hours atroom temperature. The resin was removed by filtration and washed twicewith CH₂Cl₂ (1 mL). The washings were combined with the filtrate andconcentrated in vacuo. Purification by silica gel chromatographyfollowed by characterization by LC/MS yield the title compounds.

EXAMPLE 21

[0240](S)-4-[7-(3-Ethyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid

EXAMPLE 22

[0241](S)-4-[7-(3-Isopropyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid

EXAMPLE 23

[0242](S)-2,2-Dimethyl-4-[7-(3-phenyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid

EXAMPLE 24

[0243](S)-4-[7-(3,3-Diethyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid

EXAMPLES 25-33

[0244] General Procedure for Solid Phase Synthesis of HydroxyamideDerivatives (Scheme 3).

[0245] a) To a suspension of hydroxylamine resin (1.5 g, 2.24 mmol) inDMF/CH₂Cl₂ (20 mL, 1:1) was added carboxylic acid 4 (2.6 g, 6.7 mmol)dissolved in DMF (5 mL). 1,3-Diisopropylcarbodiimide (1 mL, 6.7 mmol)and 4-(dimethylamino)pyridine (0.024 g, 0.2 mmol) were added, and theresulting mixture was shaken for 22 hours at room temperature. The resinwas filtered, washed 4 times with DMF (20 mL each) and 4 times withCH₂Cl₂ (20 mL), then dried in vacuo overnight to give resin 11.

[0246] Utilizing steps (b) and (c) of Example 16 on the resinsynthesized in (a) yield compounds of formula 13.

EXAMPLE 25

[0247](S)-4-[7-(2,4-Dichloro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carbxoylicacid hydroxyamide

EXAMPLE 26

[0248](S)-4-[7-(3,4-Dimethoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide

EXAMPLE 27

[0249](S)-4-[7-(2,5-Dimethoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide

EXAMPLE 28

[0250](S)-2,2-Dimethyl-4-(7-phenylacetylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide

EXAMPLE 29

[0251](S)-2,2-Dimethyl-4-{7-[(thiophene-2-carbonyl)-amino]-dibenzofuran-2-sulfonyl}-thiomorpholine-3-carboxylicacid hydroxyamide

[0252] Replacement of acid chloride in Example 25 with appropriatelysubstituted isocyanates yield the following urea derivatives:

EXAMPLE 30

[0253](S)-4-[7-(3-Ethyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide

EXAMPLE 31

[0254](S)-4-[7-(3-Isopropyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide

EXAMPLE 32

[0255](S)-2,2-Dimethyl-4-[7-(3-phenyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide

EXAMPLE 33

[0256](S)-4-[7-(3,3-Diethyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide

[0257] By following the general procedures described above, thefollowing invention compounds are similarly prepared:

[0258]2,2-Dimethyl-4-[7-(3-nitro-benzoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0259]4-(7-Dodecanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0260]N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-oxalamicacid ethyl ester;

[0261]4-[7-(Cyclohexanecarbonyl-amino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0262]4-[7-(2-Fluoro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0263]4-(7-Acetylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0264] Acetic acid2-[8-(3-hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-ylcarbamoyl]-phenylester;

[0265]4-(7-Benzoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0266]4-(7-Butyrylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0267]4-(7-Decanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0268]4-(7-Decanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0269]4-(7-Diphenylacetylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0270]4-{7-[2-(4-Chloro-phenoxy)-acetylamino]-dibenzofuran-2-sulfonyl}-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0271]N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-succinamicacid methyl ester;

[0272]4-[7-(3,4-Dimethoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0273]4-[7-(2-Methoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0274]4-[7-(2,2-Dimethyl-pentanoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0275]4-[7-(2,4-Dichloro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0276]4-[7-(2,5-Dimethoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0277]2,2-Dimethyl-4-[7-(4-methyl-pentanoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0278]4-[7-(Cyclopropanecarbonyl-amino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0279] Acetic acid[8-(3-hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-ylcarbamoyl]-phenyl-methylester;

[0280]2,2-Dimethyl-4-{7-[(tricyclo[3.3.1]decanane-1-carbonyl)-amino]-dibenzofuran-2-sulfonyl}-thiomorpholine-3-carboxylicacid hydroxyamide;

[0281]2,2-Dimethyl-4-(7-pentanoylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;

[0282]4-[7-(2,2-Dimethyl-propionylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0283]2,2-Dimethyl-4-[7-((Z)-octadec-9-enoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0284]N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-succinamicacid ethyl ester;

[0285]4-(7-Isobutyrylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0286]4-(7-Isobutyrylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0287]4-[7-(3-Chloro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0288]2,2-Dimethyl-4-(7-nonanoylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;

[0289]2,2-Dimethyl-4-[7-(2-trifluoromethyl-benzoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0290]2,2-Dimethyl-4-[7-(2-trifluoromethyl-benzoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0291]2,2-Dimethyl-4-(7-octanoylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;

[0292]4-(7-Hexadecanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0293]4-(7-Hexadecanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0294]2,2-Dimethyl-4-[7-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-octanoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0295]2,2-Dimethyl-4-[7-(2-phenoxy-acetylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0296]2,2-Dimethyl-4-[7-(2-phenoxy-acetylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0297]2,2-Dimethyl-4-(7-phenylacetylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;

[0298]2,2-Dimethyl-4-(7-propionylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;

[0299]2,2-Dimethyl-4-(7-tridecanoylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;

[0300]4-[7-(3,5-Dinitro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0301]N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-malonamicacid ethyl ester;

[0302]N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-malonamicacid ethyl ester;

[0303]2,2-Dimethyl-4-[7-(2,2,2-trichloro-acetylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0304]2,2-Dimethyl-4-{7-[(thiophene-2-carbonyl)-amino]-dibenzofuran-2-sulfonyl}-thiomorpholine-3-carboxylicacid hydroxyamide;

[0305]2,2-Dimethyl-4-[7-(3-phenyl-propionylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide; and

[0306]4-[7-(2-Bromo-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide.

[0307] The invention compounds of Formula I have been evaluated instandard assays for their ability to inhibit the catalytic activity ofvarious MMP enzymes. The assays used to evaluate the biological activityof the invention compounds are well known and routinely used by thoseskilled in the study of MMP inhibitors and their use to treat clinicalconditions.

[0308] The assays measure the amount by which a test compound reducesthe hydrolysis of a thiopeptolide substrate catalyzed by a matrixmetalloproteinase enzyme. Such assays are described in detail by Ye etal., Biochemistry, 1992;31(45):11231-11235, hereby incorporated hereinby reference.

[0309] Thiopeptolide substrates show virtually no decomposition orhydrolysis at or below neutral pH in the absence of a matrixmetalloproteinase enzyme. A typical thiopeptolide substrate commonlyutilized for assays is Ac-Pro-Leu-Gly-thioester-Leu-Leu-Gly-OEt. A 100μL assay mixture will contain 50 mM ofN-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid buffer (“HEPES”) atpH 7.0, 10 mM CaCl₂, 100 μM thiopeptolide substrate, and 1 mM5,5′-dithio-bis-(2-nitrobenzoic acid) (DTNB). The thiopeptolidesubstrate concentration may be varied from, for example, 10 to 800 μM,in order to obtain Km and Kcat values. The change in absorbance at 405nm is monitored on a Thermo Max microplate reader (Molecular Devices,Menlo Park, Calif.) at room temperature (22° C.). The calculation of theamount of hydrolysis of the thiopeptolide substrate is based onE₄₁₂=13600 M⁻¹ cm⁻¹ for the DTNB-derived product3-carboxy-4-nitrothiophenoxide. Assays are carried out with and withoutmatrix metalloproteinase inhibitor compounds, and the amount ofhydrolysis is compared for a determination of inhibitory activity of thetest compounds.

[0310] It should be appreciated that the assay buffer used with MMP-3CDis 50 mM of N-morpholinoethanesulfonate (“MES”) at pH 6.0 rather thanthe HEPES buffer at pH 7.0 described above.

[0311] Several representative compounds have been evaluated for theirability to inhibit various matrix metalloproteinase enzymes. Table 1below presents inhibitory activity for compounds from various classes.In Table 1, MMP-1FL refers to full-length interstitial collagenase;MMP-2FL refers to full-length Gelatinase A; MMP-3CD refers to thecatalytic domain of stromelysin-1; MMP-7FL refers to full-lengthmatrilysin; MMP-9FL refers to full-length Gelatinase B; MMP-13CD refersto the catalytic domain of collagenase 3; and MMP-14CD refers to thecatalytic domain of MMP-14. Test compounds were evaluated at variousconcentrations, in order to determine their respective IC₅₀ values, themicromolar concentration of compound required to cause a 50% inhibitionof the catalytic activity of the respective enzyme. TABLE 1 (IC₅₀ in μM)Example MMP-1FL MMP-2FL MMP-3CD MMP-7FL MMP-9FL MMP-13CD MMP-14CD 11.424 0.074 0.041 55 22.5 0.97 0.064 2 0.013 0.015 0.011 0.20 0.21 0.0040.026 3 100 9.5 2.5 100 150 23 10 4 6.9 3.9 3.2 59 18 1.4 11 5 23 0.500.13 100 100 5.1 0.84 6 0.14 0.024 0.008 0.88 0.55 0.004 0.063 7 59 3.90.21 16 100 11 4 8 0.017 0.015 0.009 0.028 0.26 0.003 0.04 9 70 4 0.021.2 65 0.92 3.8 10 0.042 0.007 0.004 0.031 0.066 0.002 0.012 11 100 5.20.094 3.5 69 4.6 20 12 0.15 0.017 0.006 0.029 0.047 0.005 0.095 13 60 331 1.6 100 2.7 15 14 0.012 0.022 0.005 0.038 0.19 0.002 0.024 15 .033 .25.008 .032 1.8 .013 .098

[0312] The foregoing data in Table 1 establish that the inventioncompounds of Formula I are potent inhibitors of MMP enzymes. Because ofthis potent inhibitory activity, the invention compounds are especiallyuseful to treat diseases mediated by the MMP enzymes.

[0313] Administration of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, to a mammal to treat diseases mediated by MMPenzymes is preferably, although not necessarily, accomplished byadministering the compound or the salt thereof, in a pharmaceuticaldosage form.

[0314] The compounds of the present invention can be prepared andadministered in a wide variety of oral and parenteral dosage forms.Thus, the compounds of the present invention can be administered byinjection, that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formula I or a correspondingpharmaceutically acceptable salt of a compound of Formula I. The activecompound generally is present in a concentration of about 5% to about95% by weight of the formulation.

[0315] For preparing pharmaceutical compositions from the compounds ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavoring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

[0316] In powders, the carrier is a finely divided solid which is in amixture with the finely divided active component.

[0317] In tablets, the active component is mixed with the carrier havingthe necessary binding properties in suitable proportions and compactedin the shape and size desired.

[0318] The powders and tablets preferably contain from 5% or 10% toabout 70% of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers,is surrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

[0319] For preparing suppositories, a low melting wax, such as a mixtureof fatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

[0320] Liquid form preparations include solutions, suspensions, andemulsions, for example, water or water propylene glycol solutions. Forparenteral injection, liquid preparations can be formulated in solutionin aqueous polyethylene glycol solution.

[0321] Aqueous solutions suitable for oral use can be prepared bydissolving the active component in water and adding suitable colorants,flavors, stabilizing, and thickening agents as desired.

[0322] Aqueous suspensions suitable for oral use can be made bydispersing the finely divided active component in water with viscousmaterial, such as natural or synthetic gums, resins, methylcellulose,sodium carboxymethylcellulose, and other well-known suspending agents.

[0323] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

[0324] The pharmaceutical preparation is preferably in unit dosage form.In such form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

[0325] The quantity of active component in a unit dose preparation maybe varied or adjusted from 1 to 1000 mg, preferably 10 to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

[0326] In therapeutic use as agents to inhibit a matrixmetalloproteinase enzyme for the treatment of atherosclerotic plaquerupture, aortic aneurism, heart failure, restenosis, periodontaldisease, corneal ulceration, cancer metastasis, tumor angiogenesis,arthritis, or other autoimmune or inflammatory disorders dependent uponbreakdown of connective tissue, the compounds utilized in thepharmaceutical method of this invention are administered at a dose thatis effective to inhibit the hydrolytic activity of one or more matrixmetalloproteinase enzymes. The initial dosage of about 1 mg/kg to about100 mg/kg daily will be effective. A daily dose range of about 25 mg/kgto about 75 mg/kg is preferred. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect under thecircumstance is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired. Typicaldosages will be from about 0.1 mg/kg to about 500 mg/kg, and ideallyabout 25 mg/kg to about 250 mg/kg, such that it will be an amount whichis effective to treat the particular disease being prevented orcontrolled.

[0327] The following examples illustrate typical pharmaceuticalcompositions provided by the invention.

COMPOSITION EXAMPLE 1

[0328] COMPOSITION EXAMPLE 1 Tablet Formulation Ingredient Amount (mg)Compound of Example 1 25 Lactose 50 Corn starch (for mix) 10 Corn starch(paste) 10 Magnesium stearate (1%) 5 Total 100

[0329] The cyclic sulfonamide of Example 1, lactose, and corn starch(for mix) are blended to uniformity. The corn starch (for paste) issuspended in 200 mL of water and heated with stirring to form a paste.The paste is used to granulate the mixed powders. The wet granules arepassed through a Number 8 hand screen and dried at 80° C. The drygranules are lubricated with the 1% magnesium stearate and pressed intoa tablet. Such tablets can be administered to a human from one to fourtimes a day for treatment of atherosclerosis and arthritis.

COMPOSITION EXAMPLE 2

[0330] COMPOSITION EXAMPLE 2 Preparation for Oral Solution IngredientAmount Sorbitol solution (70% N.F.)  40 mL Compound of Example 3 400 mgSodium benzoate  20 mg Saccharin  5 mg Red dye  10 mg Cherry flavor  20mg Distilled water q.s. 100 mL

[0331] The sorbitol solution is added to 40 mL of distilled water, andthe cyclic sulfonamide of Example 3 is dissolved therein. The saccharin,sodium benzoate, flavor, and dye are added and dissolved. The volume isadjusted to 100 mL with distilled water. Each milliliter of syrupcontains 4 mg of invention compound.

COMPOSITION EXAMPLE 3

[0332] Parenteral Solution

[0333] In a solution of 700 mL of propylene glycol and 200 mL of waterfor injection is suspended 20 g of the compound of Example 2. Aftersuspension is complete, the pH is adjusted to 6.5 with 1N sodiumhydroxide, and the volume is made up to 1000 mL with water forinjection. The formulation is sterilized, filled into 5.0-mL ampouleseach containing 2.0 mL, and sealed under nitrogen.

[0334] As matrix metalloproteinase inhibitors, the compounds of FormulaI are useful as agents for the treatment of multiple sclerosis. They arealso useful as agents for the treatment of atherosclerotic plaquerupture, restenosis, periodontal disease, corneal ulceration, treatmentof burns, decubital ulcers, wound repair, heart failure, cancermetastasis, tumor angiogenesis, arthritis, and other inflammatorydisorders dependent upon tissue invasion by leukocytes. The compoundsare especially useful to treat rheumatoid arthritis and osteoarthritis.

[0335] It should be appreciated that in all invention embodimentsdescribed above or in the claims below, whenever an R group such as, forexample, R¹, R², R³, R⁴, R⁵, or R⁶, is used more than once to define aninvention compound, each use of the R group is independent of any otheruse of that same R group or, for that matter, any other R group, unlessotherwise specified.

What is claimed is:
 1. A compound of Formula I

or a pharmaceutically acceptable salt thereof wherein: R¹ and R²independently are hydrogen or C₁-C₆ alkyl; R³ and R⁴ independently arehydrogen, halo, nitro, NR⁵R⁶, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl;(CH₂)_(m) OH, (CH₂)_(m) OR⁵, (CH₂)_(m) cycloalkyl, (CH₂)_(m) aryl,(CH₂)_(m) substituted aryl, (CH₂)_(m) heteroaryl, (CH₂)_(m) substitutedheteroaryl, (CH₂)_(m) carbocycle, (CH₂)_(m) heterocycle; (CH₂)_(m)NR⁵R⁶, NHCONR⁵R⁶, (CH₂)_(m) COR⁵, (CH₂)_(m) CONR⁵R⁶, or (CH₂)_(m) CO₂R⁵;m is an integer from 0 to 6; R⁵ and R⁶ independently are hydrogen orC₁-C₆ alkyl, or taken together with the nitrogen to which they areattached complete a 3- to 7-membered ring; Z is (CH₂)_(n); n is 0, 1, or2; Y is S, SO, or SO₂; X is OH or NHOH; V is O, S, SO₂, NH, NR⁵, or CH₂.2. A compound of Formula II

or a pharmaceutically acceptable salt thereof wherein: R¹ and R²independently are hydrogen or C₁-C₆ alkyl; R³ is hydrogen, halo, nitro,NR⁵R⁶, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl; (CH₂)_(m) OH,(CH₂)_(m) OR⁵, (CH₂)_(m) cycloalkyl, (CH₂)_(m) aryl, (CH₂)_(m)substituted aryl, (CH₂)_(m) heteroaryl, (CH₂)_(m) substitutedheteroaryl, (CH₂)_(m) carbocycle, (CH₂)_(m) heterocycle; (CH₂)_(m)NR⁵R⁶, NHCONR⁵R⁶, (CH₂)_(m) COR⁵, (CH2)_(m) CONR⁵R⁶, or (CH₂)_(m) CO₂R⁵;V is O, S, SO₂, NH, NR⁵, or CH₂; and X is OH or NHOH.
 3. A compound ofclaim 2 wherein R¹ and R² are methyl.
 4. A compound of claim 2 wherein Xis OH.
 5. A compound of claim 2 wherein X is NHOH.
 6. A compound ofFormula III

or a pharmaceutically acceptable salt thereof wherein: R¹ and R²independently are hydrogen or C₁-C₆ alkyl; R³ is hydrogen, halo, nitro,NR⁵R⁶, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl; (CH₂)_(m) OH,(CH₂)_(m) OR⁵, (CH₂)_(m) cycloalkyl, (CH₂)_(m) aryl, (CH₂)_(m)substituted aryl, (CH₂)_(m) heteroaryl, (CH₂)_(m) substitutedheteroaryl, (CH₂)_(m) carbocycle, (CH₂)_(m) heterocycle; (CH₂)_(m)NR⁵R⁶, NHCONR⁵R⁶, (CH₂)_(m) COR⁵, (CH₂)_(m) CONR⁵R⁶, or (CH₂)_(m) CO₂R⁵;and X is OH or NHOH.
 7. A compound of Formula IV

or a pharmaceutically acceptable salt thereof wherein: R¹ and R²independently are hydrogen or C₁-C₆ alkyl; R³ is hydrogen, halo, nitro,NR⁵R⁶, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl; (CH₂)_(m) OH,(CH₂)_(m) OR⁵, (CH₂)_(m) cycloalkyl, (CH₂)_(m) aryl, (CH₂)_(m)substituted aryl, (CH₂)_(m) heteroaryl, (CH₂)_(m) substitutedheteroaryl, (CH₂)_(m) carbocycle, (CH₂)_(m) heterocycle; (CH₂)_(m)NR⁵R⁶, NHCONR⁵R⁶, (CH₂)_(m) COR⁵, (CH₂)_(m) CONR⁵R⁶, or (CH₂)_(m) CO₂R⁵;and X is OH or NHOH.
 8. A compound of Formula V

 or a pharmaceutically acceptable salt thereof wherein: R¹ and R²independently are hydrogen or C₁-C₆ alkyl; R³ is hydrogen, halo, nitro,NR⁵R⁶, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl; (CH₂)_(m) OH,(CH₂)_(m) OR⁵, (CH₂)_(m) cycloalkyl, (CH₂)_(m) aryl, (CH₂)_(m)substituted aryl, (CH₂)_(m) heteroaryl, (CH₂)_(m) substitutedheteroaryl, (CH₂)_(m) carbocycle, (CH₂)_(m) heterocycle; (CH₂)_(m)NR⁵R⁶, NHCONR⁵R⁶, (CH₂)_(m) COR⁵, (CH₂)_(m) CONR⁵R⁶, or (CH₂)_(m) CO₂R⁵;and X is OH or NHOH.
 9. A compound of Formula VI

or a pharmaceutically acceptable salt thereof wherein: R¹ and R²independently are hydrogen or C₁-C₆ alkyl; R³ is hydrogen, halo, nitro,NR⁵R⁶, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl; (CH₂)_(m) OH,(CH₂)_(m) OR⁵, (CH₂)_(m) cycloalkyl, (CH₂)_(m) aryl, (CH₂)_(m)substituted aryl, (CH₂)_(m) heteroaryl, (CH₂)_(m) substitutedheteroaryl, (CH₂)_(m) carbocycle, (CH₂)_(m) heterocycle; (CH₂)_(m)NR⁵R⁶, NHCONR⁵R⁶, (CH₂)_(m) COR⁵, (CH₂)_(m) CONR⁵R⁶, or (CH₂)_(m) CO₂R⁵;and X is OH or NHOH.
 10. A compound of Formula VII

or a pharmaceutically acceptable salt thereof, wherein R¹ and R²independently are hydrogen or C₁-C₆ alkyl; R³ is hydrogen, halo, nitroNR⁵R⁵, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl; (CH₂)_(m) OH,(CH₂)_(m) OR₅, (CH₂)_(m) cycloalkyl, (CH₂)_(m) aryl, (CH₂)_(m)substituted aryl, (CH₂)_(m) heteroaryl, (CH₂)_(m) substitutedheteroaryl, (CH₂)_(m) carbocycle, (CH₂)_(m) heterocycle; (CH₂)_(m)NR⁵R⁶, (CH₂)_(m) COR⁵, (CH₂)_(m) CONR⁵R⁶, or (CH₂)_(m) CO₂R⁵; m is aninteger of from 0 to 6; R⁵ and R⁶ independently are hydrogen or C₁-C₆alkyl, or taken together with the nitrogen to which they are attachedcomplete a 3- to 7-membered ring; Z is (CH₂)_(n); n is 0, 1, or 2; X isOH or NHOH; V is O, S, SO₂, NH, NR⁵, or CH₂.
 11. A compound which is:(S)-4-(Dibenzofuran-3-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid;(S)-4-(Dibenzofuran-3-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;R-3-(Dibenzofuran-3-sulfonyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid;R-3-(Dibenzofuran-3-sulfonyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid hydroxyamide;(S)-4-(9H-Fluorene-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid;(S)-4-(9H-Fluorene-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;(S)-4-(Dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid;(S)-4-(Dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;(S)-4-(7-Bromo-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid;(S)-4-(7-Bromo-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;(S)-4-(7-Methoxycarbonyl-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid;(S)-4-(7-Methoxycarbonyl-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;(S)-2,2-Dimethyl-4-(7-nitro-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid;(S)-2,2-Dimethyl-4-(7-nitro-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;(S)-4-(Dibenzofuran-2-sulfonyl)-2,2-dimethyl-1,1-dioxothiomorpholine-3-carboxylicacid hydroxyamide;(S)-4-(7-Isobutyrylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid;(S)-2,2-Dimethyl-4-[7-(3-phenyl-propionylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid;(S)-2,2-Dimethyl-4-[7-(4-methyl-pentanoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid;(S)-4-(7-Benzoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid;(S)-2,2-Dimethyl-4-(7-propionylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid;(S)-4-[7-(3-Ethyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid;(S)-4-[7-(3-Isopropyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid;(S)-2,2-Dimethyl-4-[7-(3-phenyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid;(S)-4-[7-(3,3-Diethyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid;(S)-4-[7-(2,4-Dichloro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carbxoylicacid hydroxyamide;(S)-4-[7-(3,4-Dimethoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;(S)-4-[7-(2,5-Dimethoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;(S)-2,2-Dimethyl-4-(7-phenylacetylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;(S)-2,2-Dimethyl-4-{7-[(thiophene-2-carbonyl)-amino]-dibenzofuran-2-sulfonyl}-thiomorpholine-3-carboxylicacid hydroxyamide;(S)-4-[7-(3-Ethyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;(S)-4-[7-(3-Isopropyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;(S)-2,2-Dimethyl-4-[7-(3-phenyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;(S)-4-[7-(3,3-Diethyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;2,2-Dimethyl-4-[7-(3-nitro-benzoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;4-(7-Dodecanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-oxalamicacid ethyl ester;4-[7-(Cyclohexanecarbonyl-amino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;4-[7-(2-Fluoro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;4-(7-Acetylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide; Acetic acid2-[8-(3-hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-ylcarbamoyl]-phenylester;4-(7-Benzoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;4-(7-Butyrylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;4-(7-Decanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;4-(7-Decanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;4-(7-Diphenylacetylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;4-{7-[2-(4-Chloro-phenoxy)-acetylamino]-dibenzofuran-2-sulfonyl}-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-succinamicacid methyl ester;4-[7-(3,4-Dimethoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide; b4-[7-(2-Methoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;4-[7-(2,2-Dimethyl-pentanoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;4-[7-(2,4-Dichloro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;4-[7-(2,5-Dimethoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;2,2-Dimethyl-4-[7-(4-methyl-pentanoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;4-[7-(Cyclopropanecarbonyl-amino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide; Acetic acid[8-(3-hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-ylcarbamoyl]-phenyl-methylester;2,2-Dimethyl-4-{7-[(tricyclo[3.3.1]decanane-1-carbonyl)-amino]-dibenzofuran-2-sulfonyl}-thiomorpholine-3-carboxylicacid hydroxyamide;2,2-Dimethyl-4-(7-pentanoylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;4-[7-(2,2-Dimethyl-propionylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;2,2-Dimethyl-4-[7-((Z)-octadec-9-enoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-succinamicacid ethyl ester;4-(7-Isobutyrylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;4-(7-Isobutyrylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;4-[7-(3-Chloro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;2,2-Dimethyl-4-(7-nonanoylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;2,2-Dimethyl-4-[7-(2-trifluoromethyl-benzoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;2,2-Dimethyl-4-[7-(2-trifluoromethyl-benzoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;2,2-Dimethyl-4-(7-octanoylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;4-(7-Hexadecanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;4-(7-Hexadecanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;2,2-Dimethyl-4-[7-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-octanoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;2,2-Dimethyl-4-[7-(2-phenoxy-acetylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;2,2-Dimethyl-4-[7-(2-phenoxy-acetylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;2,2-Dimethyl-4-(7-phenylacetylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;2,2-Dimethyl-4-(7-propionylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;2,2-Dimethyl-4-(7-tridecanoylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylicacid hydroxyamide;4-[7-(3,5-Dinitro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-malonamicacid ethyl ester;N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-malonamicacid ethyl ester;2,2-Dimethyl-4-[7-(2,2,2-trichloro-acetylamino)-dibenzofuran-2-suffonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;2,2-Dimethyl-4-{7-[(thiophene-2-carbonyl)-amino]-dibenzofuran-2-sulfonyl}-thiomorpholine-3-carboxylicacid hydroxyamide;2,2-Dimethyl-4-[7-(3-phenyl-propionylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide; or4-[7-(2-Bromo-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide.
 12. A pharmaceutical composition, comprising acompound of claim 1, or a pharmaceutically acceptable salt thereof,admixed with a pharmaceutically acceptable carrier, diluent, orexcipient.
 13. A pharmaceutical composition, comprising a compound ofany one of claims 2, 6, 7, 8, 9, and 10, or a pharmaceuticallyacceptable salt thereof, admixed with a pharmaceutically acceptablecarrier, diluent, or excipient.
 14. A pharmaceutical composition,comprising a compound of claim 11, or a pharmaceutically acceptable saltthereof, admixed with a pharmaceutically acceptable carrier, diluent, orexcipient.
 15. A method for inhibiting MMP enzymes in an animal,comprising administering to the animal an MMP inhibiting amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof. 16.A method for treating cancer comprising administering to a patienthaving cancer and in need of treatment an anticancer effective amount ofa compound of claim 1, or a pharmaceutically acceptable salt thereof.17. A method for treating rheumatoid arthritis comprising administeringto a patient in need of treatment an effective amount of a compound ofclaim 1, or a pharmaceutically acceptable salt thereof.
 18. A method fortreating osteoarthritis comp rising administering to a patient in needof treatment an effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 19. A method for treating congestive heart failure comprising administering to a patient in need oftreatment an effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 20. A method for treatinginflammation, comprising administering to a patient in need of treatmentan effective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.